Cancer, known medically as a malignant neoplasm, refers to a broad group of diseases involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors and invading nearby parts of the body. The cancer may also spread to more distant parts of the body through the lymphatic system or bloodstream, through a mechanism generally known as metastasis. Not all tumors are cancerous, however. In contrast to cancerous tumors, benign tumors do not invade neighboring tissues and do not spread throughout the body.
Cancer is a highly heterogeneous disease, with over two hundred different known cancers that affect humans. The causes of cancer are diverse, complex, and only partially understood. Factors that increase the risk of cancer include tobacco use, dietary factors, certain infections, exposure to radiation, lack of physical activity, obesity, and environmental pollutants. These factors can directly damage genes or combine with existing genetic faults within cells to cause cancerous mutations. Approximately 5-10% of cancers can be traced directly to inherited genetic defects.
Cancer is the second leading cause of deaths in the U.S., and the number of deaths due to cancer continues to grow. Cancer treatment may include surgery, radiation and/or chemotherapy, based upon the type, location and dissemination of cancer. Surgery and localized radiation therapy may present lower toxicities to healthy cells and tissues, while chemotherapy is the best treatment option for disseminated cancer, leukemia, lymphoma, and metastasized cancers. Not all tumors respond to chemotherapeutic agents. Other tumors, although initially responsive to chemotherapeutic agents, may develop resistance, with cancer eventually recurring.
Various classes of chemotherapeutic agents have been described. These chemotherapeutic agents can be natural products, structurally modified natural products, or synthetic chemical or biological agents. The majority of chemotherapeutic drugs act by interfering with and/or preventing cell division, or interfering with DNA synthesis or function. Interestingly, novel tyrosine kinase inhibitors, such as imatinib mesylate (Gleevec or Glivec), target a specific molecular abnormality in specific types of cancer, and their use is thus limited to cancers that carry such abnormalities.
Angiogenesis is the physiological process through which new blood vessels form from pre-existing vessels. This is distinct from vasculogenesis, which is the de novo formation of endothelial cells from mesoderm cell precursors. Angiogenesis is a normal and vital process in growth and development, wound healing and the formation of granulation tissue. However, it is also a fundamental step in the transition of tumors from a benign state to a malignant one. Further, uncontrolled angiogenesis may damage various organs and tissues, such as eyes, skin, heart, blood vessels, lung, gastrointestinal tract and genitourinary tract. Thus, anti-angiogenesis agents (also known as angiogenesis inhibitors) may be used in the treatment of cancer and/or prevention of uncontrolled angiogenesis.
Cholesterol is a steroidal metabolite that is found in the cell membranes and transported in the blood plasma of all animals. Cholesterol is an essential structural component of mammalian cell membranes, where it is required to establish proper membrane permeability and fluidity. In addition, cholesterol is an important component for the manufacture of bile acids, steroid hormones, and fat-soluble vitamins including vitamins A, D, E and K.
Cholesterol accumulation has been reported in various solid tumors, including prostate cancer and oral cancer. In addition, cholesterol metabolism is dysregulated in many malignancies, including myeloid leukemia, lung cancer and breast cancer. Specifically, the activity of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, the rate-limiting enzyme in cholesterol biosynthesis, is up-regulated in various tumors. Malignant cells often have elevated levels of mevalonate, which formation is catalyzed by HMG-CoA, and consistently mevalonate treatment was found to promote tumor growth in vivo and to stimulate the proliferation of breast cancer cells. Cholesterol metabolism is also dysregulated in many hematopoietic malignancies, including acute myeloid leukemia. High cellular cholesterol may in fact increase leukemia cell survival and impart relative resistance to therapy.
Cholesterol derivatives include 7-dehydrocholesterol (7DHC), a provitamin D present in animals. The presence of 7DHC in skin enables humans to manufacture vitamin D3 using ultraviolet rays in the sun light. Increased levels of 7DHC and decreased levels of cholesterol were found in patients with Smith-Lemli-Opitz syndrome (SLOS), an autosomal recessive malformation syndrome associated with intellectual disability and behavioral problems. Unfortunately, only a few examples of synthetic derivatives of cholesterol are known, and their effects on biosynthetic, metabolic and catabolic pathways of cholesterol remain unexplored.
There is a need in the art to identify novel compounds that can be used to treat or prevent cancer in a subject. There is also a need in the art to identify novel compounds that can be used to treat or prevent uncontrolled angiogenesis in a subject. The present invention addresses and meets these needs.